KR20110067009A - Manufacturing method of micro needle stamper - Google Patents

Abstract

The microneedle sheet is produced by injecting a needle raw material into a stamper having a recess formed in the base material, but it is not easy to increase the sharpness of the recess corresponding to the tip of the stamper.
A step of heating a disc having a sheet-like base material and an awl-shaped protrusion, and a step of inserting the protrusion of the disc into the base material to form an awl-shaped recess. It provides a stamper manufacturing method comprising the step of cooling the original plate in the state inserted into the base material, the step of separating the original plate from the base material, and the step of heating the base material.

Description

Manufacturing method of micro needle stamper {MANUFACTURING METHOD OF MICRO NEEDLE STAMPER}

The present invention relates to a method for producing a cancer mold for producing a microneedle for injecting drugs from the epidermis.

The microneedle has a length of about 1 μm to 600 μm, and the ratio of the cross section diameter to the length of the base portion has a high aspect ratio of cross section diameter: length = 1: 1 to 1.5 to 1: 3. It is arrange | positioned at the predetermined density on (). It is used to inject drugs by inserting microneedles (hereinafter simply referred to as "needle") into the epidermal part of the skin, mainly on the skin part of the human body.

The length of the microneedle is on the order of hundreds of micrometers, so it rarely involves pain. In addition, the microneedle portion is formed of a self-dissolving substance so that even when the microneedles remain in the skin when the sheet is removed from the skin, the microneedle portion does not cause any damage to the human body.

A general manufacturing method of the microneedle sheet will be described with reference to FIG. 5. The disc 90 of the microneedle sheet is manufactured by a method such as micromachining, vacuum treatment, or photolithography. The length 93 of the needle has an awl shape of several hundred micrometers or less as described above. The cross section includes circles, angles, ellipses, and the like. Since the needle is of a small size, it is preferable to form the needle 92 by cutting the plate 92.

Next, the master plate 90 is pressed onto the base material 81 of the stamper to produce a stamper 80 (a mold of a microneedle). And the microneedle sheet 77 can be obtained by pouring the melt | dissolution liquid or drug 85 of a resin polymer into the stamper 80, and after drying, attaching to the fixed base material 88 and carrying out peeling transfer (refer patent document 1). .

Here, as a method for producing the stamper 80, there is also a method of pressing the base plate 90 onto the base material 81 instead of pressing the base plate 90, followed by pouring the resin dissolved in the base plate 90 and drying it (see Patent Document 2).

Patent Document 1: Japanese Patent Application Laid-Open No. 2008-245955 Patent Document 2: Japanese Patent Application Laid-Open No. 2008-006178 Patent Document 3: Japanese Patent Laid-Open No. 2009-083125

Since the microneedles are inserted into the skin, the tip needs to be as sharp as possible. And the microneedle sheet is produced by pouring the raw material of the needle into the produced stamper. Therefore, the bottom portion (corresponding to the tip of the microneedle) of the recess of the stamper through which the raw material flows should be a high sharpness recess. However, there existed a problem that it was not easy to form the recessed part with high sharpness with respect to a base material.

In addition, from the viewpoint of flowing the raw material of the needle into the stamper, there is a problem that the raw material of the microneedles is not easily filled in the recess of the stamper by air or surface tension because the recess of the stamper is a very small dimension.

More specifically, in FIG. 5 (c), when the solution or drug 85 of the resin polymer is poured into the stamper 81, air 72 is present in the recess of the stamper, and the air is released from the stamper. For the portion 73 where the 72 was, only the needle can be formed in an incomplete shape (Fig. 5 (d)).

This problem is also disclosed by patent documents 2 and 3. In patent document 2, when filling a stamper with a raw material, filling in a reduced pressure state is disclosed. In addition, Patent Document 3 discloses a method of pressurizing on the raw material side and filling the recess in the stamper. However, in the case of disposing a plurality of microneedles, there has been a problem that some microneedles scheduled for fabrication cannot be formed because raw materials are not filled in some recesses.

This invention is made | formed in view of the said subject, Specifically, The process of heating the disk which has a sheet-like base material and an awl-shaped processus | protrusion, and Inserting the processus | protrusion of the said disk into the said base material to form an awl-shaped recessed part Process and. It provides a stamper manufacturing method comprising the step of cooling the original plate in the state inserted into the base material, the step of separating the original plate from the base material, and the step of heating the base material.

Moreover, the stamper manufacturing method of this invention is characterized in that the process of forming the said awl-shaped recess is inserted until the protrusion of the said disc penetrates the said base material.

The present invention inserts a disk having an awl-shaped projection into a warmed stamper member to form an awl-shaped recess, and separates the disk after cooling in that state. Thus, a stress is applied to the stamper member deformed by the awl-shaped projection. The recess is formed in the remaining state. When the stamper member is heated after separating the awl-shaped projection, the stress is released and re-deformation occurs to fill the recess. This can form a high sharpness concave because the base material is re-deformed in the direction of narrowing the bottom of the concave portion.

In addition, a through hole penetrating to the opposite side of the stamper is formed in the bottom of the concave portion in advance, and a small through hole can be formed by reforming the stamper member by the above method. The recess of the stamper having the minute through hole is easily discharged even if air stays at the time of application of the microneedle member. Therefore, the raw material can be filled in the concave portions of all the stampers, so that a microneedle sheet on which a predetermined number of microneedles are formed can be obtained.

1 is a schematic diagram of a stamper of the present invention.
2 is a view showing a step of manufacturing a stamper of the present invention.
It is a figure which shows the detail of the manufacturing process of the stamper of this invention.
4 is a view showing a manufacturing process of a microneedle sheet using a stamper of the present invention.
5 is a view showing a manufacturing process of a microneedle sheet using a conventional stamper.

≪ Example 1 >

The stamper 1 of the microneedle sheet of this invention is shown in FIG. The stamper 1 is formed with an awl-shaped recess 3 in the sheet-like base material 2. The material of the base material 2 is not particularly limited, but is a material that is not contaminated well or a material that does not affect the human body as a medicine. In addition, since the stamper 1 of the present invention forms a concave portion having a sharp tip with heat shrinkage, plastics such as PTFE, polypropylene and polyethylene are preferably used.

The bottom part of the recessed part 3 is provided with the through-hole 4 which penetrates into the other surface of a base material. Since the through-hole 4 becomes a part which forms the front-end | tip of a microneedle, it is preferable that the diameter is small. Functionally, it is only necessary that the air remaining in the concave portion 3 can escape so that the raw material is filled in the concave portion 3, and a hole having a finite length diameter is not always required. That is, it may appear as if normally closed as long as the air escapes when the pressure is applied. Specifically, it is preferably tens of microns or less.

The installation density and installation distribution of the microneedles are not particularly limited and may be determined from time to time depending on the purpose and purpose. In the drawings, for the sake of simplicity, the description will be made by a stamper for producing a microneedle sheet having four microneedles.

Next, the manufacturing method of the stamper of this invention is illustrated. Referring to FIG. 2 (a), the disc 10 is formed by forming the awl-shaped protrusions 12 in the planar body 11, and the material is not particularly limited, but a metal having excellent workability is most preferably used. Can be. Moreover, in this invention, since it heats to the softening point temperature of a base material, the material which can maintain hardness at the temperature of the grade is preferable. For example, copper, aluminum, nickel, silicon or the like can be used. The projection 12 may be formed by a method using photolithography in addition to processing by cutting from the main body 11.

The protrusion 12 has a height 13 on the main body 11 with a height of about 1 μm to 600 μm. The epidermis into which drugs are injected using a microneedle sheet is formed of a stratum corneum, granule layer, a polar layer, or a basal layer. This is because the height of the microneedle may change depending on the site and the drug.

The projection 12 is formed such that the ratio of the cross-sectional diameter and the length of the base portion of the microneedle formed by the stamper becomes a needle shape having a relatively high aspect ratio of the cross-sectional diameter: length = 1: 1.5 to 1: 3. This is because the microneedles may be changed depending on the site used. There is no restriction | limiting in particular in the cross-sectional shape, A round shape, an ellipse, the square containing a square, etc. are applied preferably. In addition, a groove may be formed on the surface of the projection. This is because the microneedles reflecting the groove shape can smooth the insertion into the skin.

The thickness of the base material 2 is thinner than the length of the protrusion 12. The tip of the projection 12 penetrates the base material 2 to form the through hole 4. It can be set from the tip shape of the projection 12 and the thickness 5 of the base material 2 so that the diameter of the through-hole 4 formed in the base material 2 may be about tens of microns. In the present invention, since the through hole 4 may contract due to heat shrinkage, the through diameter 4a when the protrusion 12 of the disc 10 penetrates the base material 2 is defined as the through hole of the stamper 1. This is because it can be made larger than 4).

First, the disc 10 and the base material 2 are heated 14 previously. The heating temperature is a temperature lower than the melting temperature of the base material 2. What is necessary is just the softening point temperature of the base material 2. This is because the formation of the recessed portion of the stamper of the present invention undergoes a process of plastic deformation in a state in which stress is applied to the base material 2. If the temperature of the disc 10 is higher than the melting temperature of the base material 2, the base material 2 will melt | dissolve and cannot form the recessed part 3 according to the shape of the protrusion 12 of the disc 10. Moreover, when the temperature of the original plate 10 is too low compared with the temperature of the base material 2, the stress required at the time of reshaping does not remain.

Next, the heated original plate 10 is inserted into the heated base material 2 (FIG. 2 (b)). And the original board 10 is cooled to room temperature in the state which stuck the base material 2, and the original board 10 is isolate | separated (FIG. 2 (c)). The enlarged view of the part which the projection 12 of the original board 10 heated to FIG. 3 (a) stuck in the heated base material 2 is shown. In the part (26) in which the protrusion 12 was inserted in the base material 2, the base material is pressed and widened by the protrusion 12, so that the molecules are in a compressed state. This compressed portion is called recess surface layer 26.

Referring to FIG. 3 (b), when the disc 10 is removed after cooling (removed from the mold), the recess surface layer 26 having the through hole maintains the shape in the state where the stress 27 is accumulated. have. In FIG. 3B, the two left and right arrows are denoted by the reference numerals, but the remaining arrows also indicate stress. The through hole formed at this time is the through hole 4a.

Returning to FIG. 2 (d), the base material 2 from which the original plate 10 was separated is heated again after cooling. At this time, the temperature to be heated is around the softening point temperature, preferably below the melting temperature. It is because it can deform | transform by the stress release of a recessed surface layer as it is temperature within this range.

Referring to Fig. 3 (c), since the stress is released in the concave surface layer of the heated base material 2, the surface layer 28 moves toward the free space. The re-deformation by the heat shrinkage causes the through-holes to shrink to form concave portions with high sharpness. In addition, compared with the case where the original plate in Fig. 3B is removed, the diameter 4aφ of the through hole is reduced by shrinkage (4a). As a specific example, in the case where the base material 2 is polyethylene, the through hole can shrink from 40 μm to 10 μm in diameter when it is maintained at 90 ° C. for about 10 seconds, thereby producing a microneedle.

The microneedle sheet is produced by the stamper produced as described above. Referring to Fig. 4, the microneedle sheet is produced by applying the needle raw material 20 to the stamper 1 (Fig. 4 (a)). It is preferable that the needle raw material 20 use a material which is discharged without remaining in the body. When the microneedle sheet is removed from the skin, the needle portion may be bent or pulled out, so that the entire microneedle sheet may not be recovered. This is because the material absorbed in the body is safe. Specifically, it is preferable that the material is mainly composed of diarrhea substances. Moreover, you may mix a drug in the needle raw material previously. Here, the drug refers to a pure chemical having a physiological activity, and may include peptide protein drugs such as insulin, growth hormone, erythropoietin, and interferon, vaccine antigens, antigen proteins, polymer drugs, vitamin C, and the like. Or a substance containing these as a main component.

Referring to FIG. 4A, since the through hole 4 is formed at the bottom of the concave portion 3 of the stamper 1 of the present invention, in order to inject the needle raw material into the stamper, only the application of the needle is concave. The part is filled. That is, even if there is air 72 in the bottom part of the recessed part 3 of the stamper 1, this air is easily discharged | emitted through the through-hole 4, and the needle raw material is filled in the recessed part 3. As shown in FIG. Of course, you may pressurize 15 after apply | coating (FIG. 4 (b)). When pressurized, the air staying at the bottom of the recess 3 of the stamper can more easily escape.

In addition, the stamper 1 may be disposed on the flat support 18 formed of a porous solid, and the needle raw material 20 may be applied while applying a negative pressure 16 from the rear surface of the flat support 18 (FIG. 4 (b)). In this case as well, the needle raw material can be easily injected into the recess 3 of the stamper. Moreover, it is better to pressurize 15 on the upper surface of the flat base 18 and to apply a negative pressure 16 on the rear surface.

After apply | coating the needle raw material 20 to the stamper 1, it dries and peels from a stamper, and the microneedle sheet 30 is completed (refer FIG. 4 (d)). Peeling from the stamper 1 attaches the fixing substrate 88 to the back surface of the dry needle raw material 20 and pulls it off the stamper. When the drug is not injected into the microneedle sheet 30 peeled from the stamper, the drug is sprayed onto the needle part 31 after peeling from the stamper.

In addition, the ratio of the cross-sectional diameter and the length of the base portion of the microneedles 31 thus produced is formed so as to have an auger shape having a relatively high aspect ratio of cross-sectional diameter: length = 1: 1.5 to 1: 3.

As described above, the stamper of the present invention has a small through hole penetrating to the opposing surface of the stamper at the bottom of the concave portion forming the needle, so that even if air enters the concave portion, the needle has a high sharpness. A microneedle sheet that can be produced can be obtained.

The present invention can be widely used not only for microneedle sheets for injecting drugs into the epidermis but also for producing microprotrusions on a substrate.

1 stamper
2 base materials
3 recess
4 through hole
5 base material thickness
10 discs
11 disc body
12 turning
13 turning height
14 heating
15 pressure
16 negative pressure
18 Porous Solid Flat Base
20 needle raw material
26 recessed surface layer
27 stress
28 Movement direction of concave surface layer
30 micro needle sheets
31 needles
72 air
77 microneedle sheets
80 conventional stamper
81 conventional stamper base material
85 needle raw materials
88 fixing
90 discs
91 main unit
92 turning
93 length of protrusion

Claims (2)

Heating a disc having a sheet-like base material and an awl-shaped protrusion;
Inserting the projection of the disc into the base material to form an awl-shaped recess;
Cooling the disc in a state where the disc is inserted into the base material;
Separating the disc from the base material;
Stamper manufacturing method having a step of heating the base material. The method according to claim 1,
In the step of forming the awl-shaped recess, the projection of the disc is inserted until it penetrates the base material.

Images